Systematic inflammatory response syndrome is the designation recently established by a group of researchers to describe related conditions resulting from, for example, sepsis, pancreatitis, multiple trauma such as injury to the brain, and tissue injury, such as laceration of the musculature, brain surgery, hemorrhagic shock, and immune-mediated organ injuries. A variety of different approaches have been suggested for treating inflammatory conditions or septic (endotoxin) shock.
U.S. Pat. No. 5,308,834, issued May 3, 1994, inventors Scott et al., discloses a method said to prevent endotoxemia in a subject by administering an amount of a leukocyte protein (BPI) effective to prevent endotoxemia in the subject.
Among the therapeutic approaches, antibodies directed against endotoxin or its components have been evaluated for their utility in immunotherapy of sepsis. Murine and human monoclonal antibodies directed against the core lipopolysaccharide of the endotoxin have been reported to exert protection during Gram-negative bacterial sepsis in animals. Dunn, Transplantation, 45, 424-429 (1988). Antibodies directed against lipid A also have been reported to have a protective effect in humans. Jaspers et al., Infection, 15 Supp. 2, S89-95 (1987). Antibodies to the J5 mutant of E. coli are reported to be protective against septic shock in animals and humans. Cohen et al., Lancet, 1, 8-11 (1987); Law and Marks, J. Infect. Dis., 151, 988-994 (1985). Antibodies to endotoxin core glycolipid have been reported to prevent the serious consequences of Gram-negative infections in surgical patients. Baumgartner et al., Lancet, 2, 59-63 (1985). In addition, human monoclonal antibodies to P. aeruzinosa exotoxin A and exoenzyme S have been described as useful for this purpose. U.S. Pat. No. 4,677,070, issued Jun. 30, 1987.
Many of the toxic effects of endotoxin are mediated by cytokines, hormones, and other small molecules. Blockade of these various mediators has been used to treat sepsis. In animal models prior administration of antibody directed against TNF was reported to protect from the lethal effects of endotoxin. Beutler et al., Science, 229, 869 (1985). Also, antibody blockade experiments were reported showing that various cytokines, such as TNF, are mediators of the lethal effects of endotoxin. Tracey et al., Nature, 330, 662 (1987); Ohlsson et al., Nature, 348, 550 (1990); Heinzel, J. Immunol., 145, 2920 (1990); Doherty et al., J. Immunol., 149, 1666 (1992); Bernhagen et al., Nature, 365, 756 (1993). More recently, either polyclonal or monoclonal antibodies to a human tumor necrosis factor binding protein (TBP-I) have been described for application in modulating the response to tumor necrosis factor, such as to suppress deleterious effects of this cytokine. U.S. Pat. No. 5,359,037, issued Oct. 25, 1994, inventors Wallach et al.
The treatment of endotoxemia or sepsis by passive immunization with endotoxin neutralizing antibodies or cytokine antibodies is a relatively new approach. However, to date many of the approaches suggested for sepsis treatment have not proven very efficacious. It is likely that treatment for septicemia in the future will combine a plurality of approaches, in view of the large cascade of pro-inflammatory cytokines unleashed during the host response to infection.
Since morbidity and mortality associated with endotoxemia remains high, new adjunct therapies are being sought because septicemia remains the leading case of death in intensive care units in the United States.